Process for preparing 3-methyl-chromone



Unite 3,100,782 PROCESS FOR PREPARING 3-METI- IYL- CHROMGNE Robert Joly, Montmorency, and Robert Bucourt, Viiliersle-Bel, France, assignors to Roussel UCLAF, Socrete Anonyme, Paris, France, a corporation of France N Drawing. Filed Sept. 21, 1961, Ser, No. 139,605

Claims priority, application France June 5, 1959 t Claims. ((31. 2,60+-345.-2)

This inyention relates to a process tor the preparation of 3 -methy1 chromone by a condensation of ethyl formate and .Ohydroxypropiophenone using solutions of organozinc compounds in N,N-dialkyl amides as condensation agents.

The solutions of the organozinc compounds in N,N-dialkylamides used according to the present invention conatent stitute important reagents .for organic synthesis which are starting from o-hydroxypropiophenone and ethyl for-mate.

The condensatlon agents are solutions of organozinc be represented .by the general compounds which may formula R ZnY, in .an N,N-dialkylamide having the formula R2 wherein R and R represent lop/er alkyl adicals, R is selected from the group consisting of hydrogen, methyl and ethyl radicals, and Y is a member selected trom the group loweralkyl, halogen, methosulfate and ethosulfate radicals.

An object of the invention is the, process torthe preparation of 3-methylchromone from o-hydroxypropiop n a -et y fo mat u iz n i solu on o a i c co poun s i NN- mkuamid s This, and other objects .of the invention will become moreapparent as the description proceeds.

The process-for the preparation of the organozinc salts in solution, whichare usedas the condensation agents, is described in copending application Serial No. 11,167, now United States Patent No. 3,040,079. This process consists essentially of reacting the desired lower alkyl halide or sulfate compound directly with zinc in the presence of an N,N-dialkylamide .having the :fionrnnla 2 orgauozinc compounds for organic synthesis, and these and the other alkyl derivatives are preferred when pre paring organoninc compounds tor use as allgylating agents.

In order toactrvate the reaction, it is often advan a q s t m s a ca a st s h a he odid c the alkyl de at ve qu t The process for the preparation of the solutions of the di l i ssedsssa s a ents as ist ess nt l f h a i s l t o o low a lz h de in n N,-l I-diall;ylamide having the formula NOR:

R2 where R and R have the meaning given above, under a vacuum and solution of diallcylzinc in an N,N-dialkylamide, as described in copending application Serial No. 11,155, e United States Patent 3,040,078. IhealkylZinc halides useful in the process of our inveni ln a fis ramrl m y i btsns e methylzinc chloride, methylzinc iodide, ethylzinc bromide, n-propylzi s b m deisssmpr z n i i ma nl n br m de isoarnylzinc bromide, etc. For economy and convenience, W Pr fe to us .m h zins rom d h ot e al z inc halides, of course, are required as starting materials to produce dialleylzinc solutions useful in general alkylatio'n reactions. i

The ia k z d s llin ove w th N.N- a m e according to the process will vary concentration depending on the relative hoiling points of the two components.

, Any concentration of the solution of dialky-lzinc in .N,N-

dialkylamide containing about 3 gram-tools. per kilogram of d-ialkylzinc or less can lbeused in the various reactions. The upper limit of concentration depends on the solubility of the particular .dialkylxinc. Eor purposes of condensing ethyl formats with lohydroxypropiophenone to form 3-rnethylchromone, we prefer to use a concentratedsolution.

In the preparation of the product 3emethylchromonone, the reaction may be conducted in any number of ways. In one-method, o-hydroxypropiophenonemay be added to the solution of the dialkyl zinc or alkylzinc halide or sulfate in N,-N-dimethylformarnide While cooling. The mixture is heated to a temperature at between about 45 and 65 C. until there is no further evolution of gas. It is advantageous ifthe amount of organozinc compound used is in excess of the amount required] The reaction mixture .is thencooled to-betweenabout 5 to 20 C; and ethyl formate isadded. rue reaction is exothermic and cooling is applied for a fewhours. The mixture is then allowed to stand for several days at room temperature.

The product 'mayrthenbe separated. The excess zinc compound is decomposed with acetic acid, for example.

The mixture-is then d-ilu'ted with water, and extracted with a. suitable solvent, such as ethyl acetate, crystallized and purified by distillation.

The reaction may also be conducted by first adding the ethyl formate slowly with agitation to the dialkyl or alkylzinc-h-alide or sulfate solution. The o-hydroxypro .pi'ophenonelis thcniadded andthe mixture is heated at between aboutH45 and 65 C. until the evolution of gas ceases. The extraction of the product is conducted as described above.

The .following examples, which are non-limitingillustrateihe invention. The temperatures are indicated in degrees .centigrade.

' EXAMPLE I Preparation of aMethylzincBromide Solution 400igm. of zinc (powdenleaflets or chips) are admixed with 300 cc. of N,N dimethylformamide and 5 cc. of methyl iodide (as catalyst) and a slow stream of methyl zinc per kilogram of'solution. The p 260 to 265 gm. and contains 1.2

distillate is a solution C. and then 24 gm.

, maintaining the temperature at 45-50 C. until the zinc completely disappears, which requires approximately three hours. Toward the end of the operation, the reaction is no longer sufficiently exothermic and the reaction mixture is heated inorder to maintain the temperature constant. The methylzinc bromide solution titrates at 2.8 to 2.9 gram-mols per kilogram of solution.

EXAMPLE 11 Preparation of a Dimethylinc Solution The entire solution obtained according to Example I is placed in a conventional distillation apparatus. The

solution is then distilled under vacuum of 17 mm. Hg. The slight excess of methylbromide present in the reaction mixture is eliminated and a mixture of di-methylformamide and dimethylzinc is distilled off. The fractions which distill over up to 6 -63 C. and then from 60-63 C. to about 70 C. are collected separately. The first fraction, which is 'a'cloudy, colorless solution weighs 770 to 775 gm. and containsfrom 3 to second fraction weighs to 1.4 gram-mols of dimethylzinc per'hilogram. Th total yield based on metallic zinc is 87-93%.

Dimethylzinc may be prepared in analogous fashion starting from methylzinc iodide or methylzinc chloride in N,N-dimethylformam=ide."

EXAMPLE III Preparation of a Diethylzinc Solution A'solution of ethylzinc bromide in N,N-di-methy1 acetamide containing 3 gram-mols of ethylzinc bromide per kilogram is heated under a vacuum of 17 mm. Hg in a distilling apparatus. After elimination of a small 7 fraction of a low boiling material, approximately twodistilled oil and collected. The of diethylzinc in "N,'Ndimethyl- EXAMPLE IV Preparation of 3-Methylchromone With the Aid of a Dimethylzinc Solution (a) With preliminary action of dimethylzinc upon o-hydroxypropiophenone.19.45 gm. of o-hydroxypropiophenone are added dropwise to 107 gm. of a solution of dimethylzinc in N,N-dimethylformamide containing 3 gram-mols of dimethylzinc per kilogram, While agitating and cooling the mixture. During the introduction of the o hydroxypropiophenone, 3.450 liters of methane are evolved, i.e., one mol per mol of o-hydroxypropiophenone. Thereafter, the reaction mixture is heated at 53-55 C. until the evaluation of methane ceases, which takes approx- "imately 2 hours. The reaction mixture is cooled to 10 of ethyl formate are added all at once. A slow exothermic reaction is produced, accompanied by a slight evolution of gas. The agitation is stopped and the thirds of the solution is acetamide.

clear yellow solution isallowed to stand for a few hours on an ice-water bath. Thereafter, the solution is allowed to stan while cooling it at room temperature for 7 days. The reaction solution turns reddish orange, a crystallization appears andfinally spreads through the entire mass. 1

The excess zinc compound is decomposed by adding 41 cc. of acetic acid over a period of one hour, accompanied by agitation and'cooling. 600 'cc..of water are added and the resulting mixture is extracted several times with 3.2 gram-mols of dimethyl in a vacuum, 17.7 gm. (which is 85.5 of theory) of pure 3-methylchromone are obtained which passes over at -152 C. under a This compound hasa melting point of 71 -7 2 C.

(b) By direct action of dimethylzinc upon the reaction mixture.24.6 gm. of ethyl formate are added slowly and while agitating to 110.5 of a solution of dime-thylzinc (3 gram-mols per kilogram) in N,N-dimethylformamide. Thereafter, 19.8 gm. of o-hydroxypropiophenone are introduced'over 'a period of /2 hour. The resulting mixture is heated for two and a half hours at about 50 C. untilthe evoluati-on of gas ceases. It isthen cooled to 20 C. and the excess of zinc compound is decomposed by the addition of 42 cc. of acetic acid while cooling. The mixture is diluted with water, extracted with ethyl acetate and-crystallized as previously described. The compound is distilled in a vacuum and the fraction boiling at 150 151 C. is collected. Pure 3-methylchromone is thus obtained, having a melting point of 71 -72 C., in a yield of 17.4 gm., which is 82.5% of theory.

EX AM PLE V Preparation of S-Methylchromone With Methylzinc Bromide and at that point the reaction proceeds fairly vigorously,

The reaction mixture is cooled to maintain the temperature at about50 C. and 156 cc. of dimethylformamide are introduced over a period of one hour. The flow of methyl bromide is maintained until ail of the zinchas completely disappeared which requires- 3 /2 hours. At the end of the reaction it'is necessary to maintain the temperature at 50 C. by heating. 7

The reaction mixture is then cooled to 30 C. and 67.5 cc. of ethyl fonmate are introduced over a period of 10 minutes. 50 gm. of then added ower a period of one hour. A reaction develops which is accompanied by the evtolution' of methane.

Thereaiiter, the reaction mixture is heated to- 60' C. until the evolution of gas ceases, which requires approximately three hours. The mixture is cooled to 20 C. and the excess of methylzinc of sodium bicarbonate and again with water. After drysol-vent'is dis'tilledolf in a a thickoil. This oil is dising over sodium sulfate the vacuum (to yield 50.9 gm. of tilled in a vacuum first fraction having a boiling range up to 148 C. and 37.5 gm. of principal traction having a boiling range of 148 to 150 C. The principal fraction (yield=70%) is practically pureB-methylchronrone having a melting point of 7172 C. The first traction ismade up of 3- methylchrornone contaminated with a small amount of o hydroxypropiophenone. The first fraction is subjected to a treatment with 10 cc. of 1N sodium hydroxide by trituration. The mixture is then vacuumfiltered, the filter cake is washed with water and dried at. 405 0 C. to give 5.875 gm. (which is 11%) of 3-methylchromone melting at 71-72 C., or an overall yield of about 81%.

For optimum resultsin utilizing the solution of an organozinc salt in an N,Ndialkylamide it is preferable to maintain a fairly concentrated solution. The concentration should be above about 0.1 mol oat organozinc salt pressure of 17 mm. of mercury.

o-hydroxypropiophenone are bromide is decomposed by the very 7 slow addition of 88 cc. of acetic acid. Thereaifiter the (17 mm. Hg) to obtain 6.2 gm. oi? a for every kilogram of solution and below the saturation point for the particular organozinc salt. For use in chemical synthesis, however it is obvious that more dilute solutions may be employed at the expense of reaction speed and completeness.

The preceding examples are illustrative of the invention. It is to be understand, however, that various changes and modifications can be made without departing from the spirit of the invention or the scope of the appended claims.

We claim:

1. In the process or preparing 3-methylchromone by the condensation of ethyl formate lwith o hydroxypropio phenone in the presenceoi an organozinc compound, the improvement which comprises condensing said ethyl tormate with said o-hydroxypropiophenone in the presence of an excess a stable solution of an organozinc compound having the formula R ZnY, in an N,N-dialkylamide having the formula /Ni) R3 2 improvement which comprises condensing said ethyl forrnate with said o-hydroxypropiophenone in the presence of a 25 to 100 percent excess of the stoichiometric amount of a stable solution of an organozinc compound having the formula R ZnY, in an N,N-dial-kylamide having the formula i R: O

wherein R and R represent lower alkyl, R is a member selected from the group consisting of hydrogen, methyl and ethyl, and Y a member selected from the group consisting of lower alkyl, halogen, methosuliate 6 and ethosultate said condensation being conducted at a temperature between about 45 and C.

3. In the process of preparing 3-methylchnornone by the condensation of ethyl formate with 1o-hydroxypropiophenone under anhydrous conditions in the presence of an organozinc compound, [the improvement which comprises condensing said ethyl formate with said o-hydroxypropiophenone in the presence of a 25 to percent excess of the stoichiometric amount of a stable solution of an organozinc compound having the formula R ZnY, in an N,N-d-ialkylamide having the formula wherein R and R represent lower alkyl, R is a member selected from the group consisting of hydrogen, methyl and ethyl, and Y is a member selected from the group consisting of lower alkyl, halogen, methosulfate and ethosulfate said condensation being conducted alta temperatm'e between about 45 and 65 C.

4. In the pnocess or preparing 3-methylchromone by the condensation of ethyl formate with o-hydroxypropiophenone under anhydrous conditions in the presence of an organozinc compound, the improvement which comprises condensing said ethyl fol-mate with said o-hydroxypropiophenone in the presence of a 25 to 100 percent excess of the stoichiometric amount of a stable solution of dimethyl zinc in dimethylformamide said condensation being conducted at a temperature between about 45 and 65 C.

5. In the process of preparing S-methylchromone by the condensation of ethyl =fiorrnate with o-hydroxypropiophenone under anhydrous conditions in the presence of an crganozinc compound, the improvement which comprises condensingsaid ethyl f-ormate with said o-hydroxy-.

propiophenone in the presence of a 25 to 100 percent excess lof the stoichiometric amount of a stable solution of methyl zinc halide dimethylformamide said condensation being conducted at a temperature between about 45 and 65 C.

References Cited in the file of this patent UNITED STATES PATENTS 2,769,015 Mentzer Oct. 30, 6

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent- N00 3,100,782 August 13, 1963 Robert Joly et a1.

It is hereby certified that error appears in the above numbered paten't requiring correction and that the said Letters Patent should read as corrected below Column 3, line 18, for "Dimethylinc" read Dimethylzinc line 61, for "evaluation" read evolution column 4, line 17, for "evoluation" read evolution Signed and sealed this 25th day of February 1964,

(SEAL) Attest:

ERNEST W, SWIDER EDWIN L. REYNOIDS Attesting Officer AC ting Commissioner of Patents 

1. IN THE PROCESS OF PREPARING 3-METHYLCHROMONE BY THE CONDENSATION OF ETHYL FORMATE WITH O-HYDROXYPROPIOPHENONE IN THE PRESENCE OF AN ORGANDZING COMPOUND, THE IMPROVEMENT WHICH COMPRISES CONDENSING SAID ETHYL FORMATE WITH SAID O-HYDROXYPROPIOPHENONE IN THE PRESENCE OF AN EXCESS A STABLE SOLUTION OF AN ORGANOZING COMPOUND HAVING THE FORMULA R1ZNY, IN AN N,N-DIALKYLAMIDE HAVING THE FORMULA 